Problems relating to the control of serum sugar levels are commonplace in modem industrialized countries. Some diseases relating to sugar levels result from insufficient endogenous insulin, others from so-called insulin insensitivity, and still other conditions from excess levels of insulin. Many of these problems are encompassed within the clinical term, diabetes mellitus, which relates to hyperglycemia, and ranges from late onset forms which can often be controlled by diet and exercise, to forms which are completely dependent on exogenous supplies of insulin or other glucose lowering drugs.
There are numerous known agents for modulating glucose levels in mammals, all of which are generically referred to herein as glycoregulatory compounds, drugs or pharmaceuticals. Among the most widely recognized glycoregulatory compounds are insulin and insulin derivatives, sulphonylurea derivatives, bisguanidine derivatives, reductase inhibitors, K-glucosidase inhibitors, and guar gum. While many of these agents are able to decrease blood glucose levels by at least 20% related to basal levels (Campbell J et al: Acad Press and Royal Society of Medicine, London 1980; McEvoy, American Hospital Pharmacy Association, 1990), only representatives from the first three groups are commonly prescribed. (see, for example, McEvoy: American Hospital Pharmacy Association, 1990, Physician Desk Reference, 1996,; British National Formulary, British Medical Association, London, 1996; Varagic, V., "Farmakologija", Medicinska Knjiga, Beograd, 1996).
One of the greatest problems in treating blood sugar level diseases is not lack of glycoregulatory agents, but administration of such agents. All mammals are thought to regulate blood sugar levels within fairly narrow ranges, and such regulation needs to be almost continuous to adequately compensate for widely varying factors such as intake of sugary foods, and the effects of corticosteroids and other hormones. Continuous, or at least frequent regulation of serum sugar levels presents considerable difficulty from an administration point of view, and many diabetics, for example, find that they need to take insulin on a daily basis. In some instances even daily insulin injections are only partially successful in properly modulating sugar levels, and in any event frequent injections of insulin leads to poor patient compliance. Even where patient complience is satisfactory, a program of frequent injections is extremely undesirable for many reasons, including pain and other effects at the injection sites.
Oral administration of glycoregulatory compounds is known. Unfortunately, all known glycoregulatory agents suffer unacceptable degradation in the gastrointestinal tract, or are problematic for some other reason. (Lee, V. H. L. and Yamamoto, A., Adv. Drug Delivery Rev., 4,171,1990). Absorption across buccal, conjunctival, rectal, vaginal and other mucous membranes are also known as alternative routes to parenteral and oral administration, but the results have generally been unsatisfactory due to poor absorption or local toxicity effects. Insulin is a classic example. Buccal absorption of insulin is minimal in the absence of an absorption enhancing agent, and similar findings have been reported for insulin absorption across the rectal mucosa.
There are several known absorption enhancing agents for trans-mucosal delivery of drugs, including bile acid salts, surfactants, chelating agents, and fatty acid derivatives. Very recently, U.S. Pat. No. 5,661,130 to Meezan et al. (August 1997) suggested the use of nonionic alkyl glycosides as drug absorption enhancing agents.
The use of bile acids and other surfactants to enhance the absorption of peptide drugs (mainly of insulin) started as early as 1932 (Collens, W. S., and Goldzieher, M. A., Proc. Soc. Exp. Biol. Med. 29,756,1932). Bile acid salts are known to improve trans-membrane uptake of endogenous and exogenous lipids in gastrointestinal tract, as well as trans-membrane or para-cell passage of small polar endogenous and exogenous molecules, such as water and inorganic electrolytes (Carey, M. C., in The Liver: Biology and Pathobiology, Eds. Arias, I. M., Popper, H., Schacter, D., Shafritz, D., Raven Press, New York, 1982, p.429), polyethylene glycol (Tagesson, C., and Sjodahl, R., Eur. Surg. Res. 16, 274,1984) and oxalates (Dobbins, J. W., and Binder, H. J., Gastroenterology 70, 1096,1976). The enhancing effect of bile acid salts upon nasal insulin absorption of insulin has been extensively studied in man (Moses, A. C., Gordon, G. S., Carey, M. C., Flier, J. S., Diabetes 32,1040,1983; Pontiroli, A. E., Alberetto, M., Secchi, A., Dossi, G., Pozza, G., Br. Med. J., 284, 303, 1982; Gordon, G. S., Moses, A. C., Silver, R. D., Flier, J. S. and Carey C. M., Proc. Natl. Acad. Sci. U.S.A. 82, 7419,1985), as well as in other laboratory animals: in rats (Hirai, S., Yashiki, T., Miama, H., Int. J. Pharm 9, 165, 1981; Yamamoto, A., Morita, T., Hashida, M. Sezaki, H., Int. J. Pharm., 93,91, (1993)), and in rabbits Duchateau, G., Zuidema, J., Merkus, F. Int. J. Pharm., 31, 193, 1986; Duchateau, G., Zuidema, J., Basseleur, S., Int. J. Pharm., 39,87,1987; Kubo, H., Hosoya, K., Natsume, H., Sugibayashi, K. Morimoto, Y., Int. J. Pharm., 103,27,1994)).
Many different bile acids have been tested for effectiveness as trans-mucosal absorption enhancers, including deoxycholic acid, cholic acid, taurocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid and chenodeoxycholic acid. Of these, the most promising effect was found with deoxycholic acid (in nasal insulin absorption), and with cholic acid (in nasal gentamycicn absorption). Even in these instances, however, absorption efficiency is low, and the quantities of bile acids used have been reported to result in unsatisfactory local and systemic toxicity. (Moses et al., Gordon et al., Salzmann et al. and Chadwick, U.S. et al., Gut, 17:10-17 (1976)).
In short, there is still a need to provide new glycoregulatory agents and means of administering such agents.